Inhibition of cardiomyocyte Sprouty1 protects from cardiac ischemia–reperfusion injury
|Author:||Alakoski, Tarja1; Ulvila, Johanna1; Yrjölä, Raisa1;|
1Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
2University of Florida Health Cancer Center, Gainesville, USA
3Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 1.3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2019060618855
|Publish Date:|| 2019-01-11
Sprouty1 (Spry1) is a negative modulator of receptor tyrosine kinase signaling, but its role in cardiomyocyte survival has not been elucidated. The aim of this study was to investigate the potential role of cardiomyocyte Spry1 in cardiac ischemia–reperfusion (I/R) injury. Infarct areas of mouse hearts showed an increase in Spry1 protein expression, which localized to cardiomyocytes. To investigate if cardiomyocyte Spry1 regulates I/R injury, 8-week-old inducible cardiomyocyte Spry1 knockout (Spry1 cKO) mice and control mice were subjected to cardiac I/R injury. Spry1 cKO mice showed reduction in release of cardiac troponin I and reduced infarct size after I/R injury compared to control mice. Similar to Spry1 knockdown in cardiomyocytes in vivo, RNAi-mediated Spry1 silencing in isolated cardiomyocytes improved cardiomyocyte survival following simulated ischemia injury. Mechanistically, Spry1 knockdown induced cardiomyocyte extracellular signal-regulated kinase (ERK) phosphorylation in healthy hearts and isolated cardiomyocytes, and enhanced ERK phosphorylation after I/R injury. Spry1-deficient cardiomyocytes showed better preserved mitochondrial membrane potential following ischemic injury and an increase in levels of phosphorylated ERK and phosphorylated glycogen synthase kinase-3β (GSK-3β) in mitochondria of hypoxic cardiomyocytes. Overexpression of constitutively active GSK-3β abrogated the protective effect of Spry1 knockdown. Moreover, pharmacological inhibition of GSK-3β protected wild-type cardiomyocytes from cell death, but did not further protect Spry1-silenced cardiomyocytes from hypoxia-induced injury. Cardiomyocyte Spry1 knockdown promotes ERK phosphorylation and offers protection from I/R injury. Our findings indicate that Spry1 is an important regulator of cardiomyocyte viability during ischemia–reperfusion injury.
Basic research in cardiology
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
Open access funding provided by University of Oulu including Oulu University Hospital. We thank Marja Arbelius, Kirsi Salo and Sirpa Rutanen for excellent technical assistance. This work was supported by Academy of Finland Grant no. 256908 to J.U., 268505 to J.M., and Grants 131020 and 297094 to R.K., by the Finnish Foundation for Cardiovascular Research (to T.A., J.U., L.V., J.M., Z.S. and R.K.), by Finnish Cultural Foundation (T.A.), by Aarne Koskelo Foundation (T.A.), by Emil Aaltonen Foundation (J.U.), by Orion Research Foundation (J.U.), by Sigrid Juselius Foundation (R.K.) and by Jane and Aatos Erkko Foundation (R.K.).
|Academy of Finland Grant Number:||
256908 (Academy of Finland Funding decision)
268505 (Academy of Finland Funding decision)
© The Author(s) 2019
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